Lung cancer is one of the most common lethal human tumors. Non-small-cell lung cancer (NSCLC) is the most common form, accounting for nearly 80% of lung tumors (American Cancer Society, Cancer Facts and Figures 2001, Am. Chem. Soc. Atlanta, 2001). The majority of NSCLCs are not diagnosed before advanced stage, and thus the overall 10-year survival rate has stayed as low as 10%, despite recent advances in multimodality therapies (Fry et al, Cancer 86: 1867-76, 1999). Currently, chemotherapy using platinum is considered to be a fundamental therapy for NSCLCs. However, the therapeutic action of pharmaceutical agents has not progressed beyond the point of being able to prolong the survival of advanced NSCLC patients to a certain extent (Non-small Cell Lung Cancer Collaborative Group, Bmj 311: 899-909, 1995). A number of targeting therapies are being investigated, including those that use tyrosine kinase inhibitors. However, to date, promising results have been achieved only in a limited number of patients, and in some patients, therapeutic effects have accompanied severe side effects (Kris et al., Proc Am Soc Clin Oncol 21: 292a (A1166), 2002).
Colorectal carcinoma is a leading cause of cancer deaths in developed countries. Specifically, more than 130,000 new cases of colorectal cancer in USA are reported each year. Colorectal cancer represents about 15% of all cancers. Of these, approximately 5% are directly related to inherited genetic defects. In spite of recent progress in therapeutic strategies, prognosis of patients with advanced cancers remains very poor. Although molecular studies have revealed the involvement of alterations in tumor suppressor genes and/or oncogenes in carcinogenesis, the precise mechanisms still remain to be elucidated.
Pancreatic cancer has one of the highest mortality rates of any malignancy, and the 5-year-survival rate of patients is 4%. 28,000 people are diagnosed as having pancreatic cancer each year, and nearly all of these patients die of their disease (Greenlee R T et al., Cancer statistics, 2001. CA Cancer J Clin 51: 15-36, 2001). The poor prognosis of this malignancy is a result of the difficulty of early diagnosis and poor response to current therapeutic methods (Greenlee R T et al., Cancer statistics, 2001. CA Cancer J Clin 51: 15-36, 2001; Klinkenbijl J H et al., Ann Surg 230: 776-82, and discussion 782-4, 1999). In particular, currently no tumor marker is identified that allows reliable screening at an early, potentially curative stage of the disease.
Prostate cancer (PRC) is one of the most common malignancies in men and represents a significant worldwide health problem. It is the second most frequent cause of cancer death in USA (Greenlee R T et al., Cancer statistics, 2001 CA Cancer J Clin 51: 15-36, 2001). Incidence of PRC is steadily increasing in developed countries according to the prevalence of Western-style diet and increasing number of senior population. Increasing number of patients also die from this disease in Japan due to adoption of a Western life style (Kuroishi T, Epidemiology of prostate cancer. Klinika 25: 43-8, 1995). Currently, the diagnosis of PRC is based on an increased level of the serum prostate specific antigen (PSA). Early diagnosis provides an opportunity for curative surgery. Patients with organ confined PRC are usually treated and approximately 70% of them are curable with radical prostatectomy (Roberts W W et al., Urology 57: 1033-7, 2001; Roberts S G et al., Mayo Clin Proc 76: 576-81, 2001). Most of patients with advanced or relapsed disease are treated with androgen ablation therapy due to the androgen-dependent initial growth of PRC. Although most of these patients initially respond to androgen ablation therapy, the disease eventually progresses to androgen-independent PRC, at which point the tumor is no longer responsive to androgen ablation therapy.
One of the most serious clinical problems in the treatment for PRC is that this androgen-independent PRC is unresponsive to any other known therapies. Thus, clarifying the mechanism of androgen-independent growth and establishing new therapies other than androgen ablation therapy against PRC are urgent issues for the management of PRC.
Breast cancer, a genetically heterogeneous disease, is the most common malignancy in women. An estimation of approximately 800,000 new cases is reported each year worldwide (Parkin D M, et al., CA Cancer J Clin 49: 33-64, 1999). Mastectomy is the first concurrent option for the treatment of this disease. Despite surgical removal of the primary tumors, relapse at local or distant sites may occur due to micrometastasis that is undetectable at the time of diagnosis (Saphner T, et al., J Clin Oncol 14: 2738-46, 1996). Cytotoxic agents are usually administered as adjuvant therapy after surgery aiming to kill those residual or premalignant cells.
Treatment with conventional chemotherapeutic agents is often empirical and is mostly based on histological tumor parameters, and in the absence of specific mechanistic understanding. Target-directed drugs are therefore becoming the bedrock treatment for breast cancer. Tamoxifen and aromatase inhibitors, two representatives of its kind, have been proved to achieve great responses when used as adjuvant or chemoprevention in patients with metastasized breast cancer (Fisher B et al. J Natl Cancer Inst 90: 1371-88, 1998; Cuzick J, Lancet 360: 817-24, 2002). However, the drawback is that only patients who express estrogen receptors are sensitive to these drugs. Further, regarding their side effects, long term tamoxifen treatment may cause endometrial cancer as well as deleterious effect of bone fracture in the postmenopausal women in aromatase prescribed patients (Coleman R E Oncology 18(5 Suppl 3): 16-20, 2004). Owing to the emergence of side effects and drug resistance, it is obviously necessarily to search novel molecular targets for selective smart drugs on the basis of characterized mechanisms of action.
Gastric cancer is a leading cause of cancer death in the world, particularly in the Far East, with approximately 700,000 new cases diagnosed worldwide annually. Surgery is the mainstay in terms of treatment, because chemotherapy remains unsatisfactory. Gastric cancers at an early stage can be cured by surgical resection, but prognosis of advanced gastric cancers remains very poor.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and its incidence is gradually increasing in Japan as well as USA (Akriviadis E A et al., Br J Surg 85(10): 1319-31, 1998.). Although recent medical advances have made great progress in diagnosis, a large number of patients with HCCs are still diagnosed at advanced stages and their complete cures from the disease remain difficult. In addition, since patients with hepatic cirrhosis or chronic hepatitis have a high risk to HCCs, they may develop multiple liver tumors, or new tumors even after complete removal of initial tumors. Therefore, development of highly effective chemotherapeutic drugs and preventive strategies are matters of pressing concern.
Research aiming at the elucidation of carcinogenic mechanisms has revealed a number of candidate target molecules for anti-tumor agents. For example, the farnesyltransferase inhibitor (FTI) is effective in the therapy of Ras-dependent tumors in animal models (Sun J. et al., Oncogene.; 16:1467-73, 1998.). This pharmaceutical agent was developed to inhibit growth signal pathways related to Ras, which is dependant on post-transcriptional farnesylation. Human clinical trials where anti-tumor agents were applied in combination with the anti-HER2 monoclonal antibody trastuzumab with the aim of antagonizing the proto-oncogene HER2/neu have succeeded in improving clinical response, and improved the overall survival rate of breast cancer patients.
Tyrosine kinase inhibitor STI-571 is an inhibitor which selectively deactivates bcr-abl fusion protein. This pharmaceutical agent was developed for the therapy of chronic myeloid leukemia, where the constant activation of bcr-abl tyrosine kinase has a significant role in the transformation of white blood cells. Such pharmaceutical agents are designed to inhibit the carcinogenic activity of specific gene products (O'Dwyer M E & Druker B J. Curr Opin Oncol.; 12:594-7, 2000.). Today, gene products with promoted expression in cancer cells are usually potential targets for the development of novel anti-tumor agents.
Another strategy for cancer therapy is the use of antibodies which bind to cancer cells. The following are representative mechanisms of antibody-mediated cancer therapy:
(I) Missile therapy: in this approach, a pharmaceutical agent is bound to an antibody that specifically binds to cancer cells, and the agent then specifically acts on the cancer cells. Through this method the pharmaceutical agent intensively acts on the cancer cells, therefore, even agents with strong side effects can be used with less side effects. In addition to pharmaceutical agents, there are also reports of approaches where precursors of pharmaceutical agents, enzymes which metabolize the precursors to an active form, and so on are bound to the antibodies;
(II) The use of antibodies which target functional molecules: this approach inhibits the binding between growth factors and cancer cells using, for example, antibodies that bind to growth factor receptors or growth factors. Some cancer cells proliferate depending on the activity of growth factors. For example, cancers dependent on epithelial growth factor (EGF) or vascular endothelial growth factor (VEGF) are known. For such cancers, inhibiting the binding between a growth factor and the cancer cells can be expected to have a therapeutic effect; and
(III) Antibody cytotoxicity: antibodies that bind to some kinds of antigens on cancer cells can exert cytotoxicity to the cancer cells. These types of antibodies have itself a direct anti-tumor effect. Antibodies that display cytotoxicity to cancer cells are gaining attention as antibody agents expected to be highly effective against tumors.
The object and features of the present invention will become more fully apparent when the following disclosure of the invention is read in conjunction with the accompanying figures and examples. However, it is to be understood that the following disclosure is of preferred embodiments, and not restrictive of the invention or other alternate embodiments of the invention.